Depression is a major public health problem among youth, currently estimated to impact between 1% to 9% of U.S. children and adolescents and twice as many females as males. Researchers have explored gene- environment interactions (GxE) in order to more deeply understand the complex etiology of depression. Despite advances, knowledge remains limited on how genetic and environmental factors combine to contribute to depression. Moreover, the field's conceptualization of "environment" is sorely narrow;very little empirical work has tried to understand the salience of both proximal and distal environments and how both types of environments interact with genetic risks. These gaps in knowledge are problematic;without a more inclusive understanding of the role of "environment," GxE research may ignore environmental risks and pathogens important in the lives of youth. Guided by a "cells to society" approach, this study will use data (Waves I - IV) from the National Longitudinal Study of Adolescent Health (Add Health), a nationally- representative study of youth ages 12-19 at enrollment, to investigate the following aims: (1) examine whether three genes found to be linked to depression (SLC6A4, DATI, DRD4) modify the association between proximal family environments (characterized by parental abuse and maltreatment of the child and low perceived closeness between parent and child) and depression in adolescents;(2) explore, after controlling for individual risks and family environments, the independent contribution of distal environments (schools and neighborhoods) on youth depression and disentangle the unique effect of these environments;(3) investigate whether SLC6A4, DAT1, and DRD4 modify the association between distal environments (schools/neighborhoods) and depression in adolescents. These aims will be accomplished using Add Health's unique genetically-informative, multi-level, longitudinal design. These aims are aligned with NIMH's Strategic Plan: Strategy 1.2 ("Identify the genetic and environmental factors associated with mental disorders") and Strategy 2.3 ("Develop tools to better define/identify risk and protective factors for mental illness across the lifespan") and the Division of Developmental Translational Research (DDTR), whose high priority is to "test integrative models incorporating biological, behavioral, and experiential factors in the development of psychopathology, and utilize longitudinal research to track trajectories of risk and protection based on the combined and interactive influences among these factors." Results of this innovative, multi- level study will advance interdisciplinary knowledge on how to measure environment and when and where to intervene in the lives of youth to reduce their risk depression and promote their resilience.